Oseltamivir is contraindicated for people aged 10-19 in principle in Japan, due to concern about abnormal behaviours. Sudden death is another concern. This review examines growing evidence of their association and discusses underlying mechanisms of these sudden-onset type reactions to oseltamivir. First, the importance of animal models and the concept of human equivalent dose (HED) is summarized. Second, the specific condition for oseltamivir use, influenza infection, is reviewed. Third, findings from toxicity studies conducted prior to and after the marketing of oseltamivir are reported on to provide context on the observation of a possible causal association. Fourth, similarity and consistency of toxicity in humans with that in other animals is described. Finally, coherence of toxicokinetic and molecular level of evidence (channels, receptors and enzymes), including differences from the toxicity of other neuraminidase inhibitors, is reviewed. It is concluded that unchanged oseltamivir has various effects on the central nervous system (CNS) that may be related to clinical findings including hypothermia, abnormal behaviours including with fatal outcome, and sudden death. Among receptors and enzymes related to CNS action, it is known that oseltamivir inhibits nicotinic acetylcholine receptors, which are closely related to hypothermia, as well as human monoamine oxidase-A (MAO-A), which is closely related to abnormal or excitatory behaviours. Receptors such as GABAA , GABAB and NMDA and their related receptors/channels including Na(+) and Ca(2+) channels are thought to be other candidates for investigation related to respiratory suppression followed by sudden death and psychotic reactions (both acute and chronic), respectively.
Background. The impact of neuraminidase inhibitors (NAI) treatment on clinical outcomes of public health importance during the 2009-10 pandemic has not been firmly established.Methods. We conducted a systematic review and meta-analysis, searching 11 databases (2009 through April 2012) for relevant studies. We used standard methodology conforming to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Pooled odds ratios (OR) and 95% confidence intervals (CI) were estimated using random effects models.Results. Regarding mortality we observed a non-significant reduction associated with NAI treatment (at any time) vs none (OR, 0.72 [95% CI, 0.51 - 1.01]). However we observed significant reductions for early treatment (≤48h after symptom onset) vs late (OR, 0.38 [95% CI, 0.27 - 0.53]); and for early treatment vs none (OR, 0.35 [95% CI, 0.18 - 0.71]). NAI treatment (at any time) vs none was associated with an elevated risk of severe outcome (OR, 1.76 [95% CI, 1.22 - 2.54]); but early treatment vs. late reduced the likelihood (OR, 0.41 [95% CI, 0.30 - 0.56]).Conclusions. During the 2009-10 influenza A(H1N1) pandemic, early initiation of NAI treatment reduced the likelihood of severe outcomes compared with late or no treatment.Prospero Registration. CRD42011001273.
To assess the effectiveness of neuraminidase inhibitors for use in rapid containment of influenza.
Industry funding and financial conflicts of interest may contribute to bias in the synthesis and interpretation of scientific evidence.
Full-genome analysis was conducted on the first isolate of a highly pathogenic avian influenza A(H5N1) virus from a human in North America. The virus has a hemagglutinin gene of clade 184.108.40.206c and is a reassortant with an H9N2 subtype lineage polymerase basic 2 gene. No mutations conferring resistance to adamantanes or neuraminidase inhibitors were found.
Oseltamivir is recommended for the treatment and prophylaxis of influenza in persons at higher risk for influenza complications such as individuals with diabetes, neuropsychiatric illnesses, and respiratory, cardiac, renal, hepatic or haematological diseases. However, a recent Cochrane review reported that reduction of antibody production, renal disorders, hyperglycaemia, psychiatric disorders, and QT prolongation may be related to oseltamivir use. The underlying mechanisms are reviewed. There is decisive evidence that administration of a clinically compatible dose of oseltamivir in mice challenged by a respiratory syncytial virus (RSV) that lacks a neuraminidase gene showed symptom-relieving effects and inhibition of viral clearance. These effects were accompanied by decreased level of T cell surface sialoglycosphingolipid (ganglioside) GM1 that is regulated by the endogenous neuraminidase in response to viral challenge. Clinical and non-clinical evidence supports the view that the usual dose of oseltamivir suppresses pro-inflammatory cytokines such as interferon-gamma, interleukin-6, and tumour necrosis factor-alpha almost completely with partial suppression of viral shedding in human influenza virus infection experiment. Animal toxicity tests support the clinical evidence with regard to renal and cardiac disorders (bradycardia and QT prolongation) and do not disprove the metabolic effect. Reduction of antibody production and cytokine induction and renal, metabolic, cardiac, and prolonged psychiatric disorders after oseltamivir use may be related to inhibition of the host’s endogenous neuraminidase. While the usual clinical dose of zanamivir may not have this effect, a higher dose or prolonged administration of zanamivir and other neuraminidase inhibitors may induce similar delayed reactions, including reduction of the antibody and/or cytokine production.
Controversy has arisen regarding the effectiveness of neuraminidase inhibitors (NIs), especially against influenza-related complications. A literature search was performed to critically assess the evidence collected by the available systematic reviews (SRs) regarding the benefits and disadvantages of NIs (oseltamivir, zanamivir) compared to placebos in healthy and at-risk individuals of all ages for prophylaxis and treatment of seasonal influenza. A SR was done using the Cochrane Database of Systematic Reviews, Health Technology Assessment Database, Database of Abstracts of Reviews of Effects, and Medline (January 2006-July 2012). Two reviewers selected SRs based on randomized clinical trials, which were restricted to intention-to-treat results, and they assessed review (AMSTAR) and study quality indicators (GRADE). The SRs included (N = 9) were of high quality. The efficacy of NIs in prophylaxis ranged from 64% (16-85) to 92% (37-99); the absolute risk reduction ranged from 1.2% to 12.1% (GRADE moderate to low). Clinically relevant treatment benefits of NIs were small in healthy adults and children suffering from influenza-like illness (GRADE high to moderate). Oseltamivir reduced antibiotic usage in healthy adults according to one SR, but this was not confirmed by other reviews (GRADE low). Zanamivir showed a preventive effect on antibiotic usage in children (95% (77-99);GRADE moderate) and on the occurrence of bronchitis in at-risk individuals (59% (30-76);GRADE moderate). No evidence was available on the treatment benefits of NIs in elderly and at-risk groups and their effects on hospitalization and mortality. In oseltamivir trials, nausea, vomiting and diarrhea were significant side-effects. For zanamivir trials, no adverse effects have been reported. The combination of diagnostic uncertainty, the risk for virus strain resistance, possible side effects and financial cost outweigh the small benefits of oseltamivir or zanamivir for the prophylaxis and treatment of healthy individuals. No relevant benefits of these NIs on complications in at-risk individuals have been established.
The impact of neuraminidase inhibitors (NAIs) on Influenza-related pneumonia (IRP) is not established. Our objective was to investigate the association between NAI treatment and IRP incidence and outcomes in patients hospitalised with A(H1N1)pdm09 virus infection.
Influenza virus is a pathogen that causes morbidity and mortality worldwide. Whereas vaccination is important for prevention of disease, given its limitations, antiviral therapy is at the forefront of treatment and also plays a role in prevention. Currently, two classes of antiviral medications, the adamantanes and the neuraminidase inhibitors, are approved for treatment. Given the resistance patterns of circulating influenza, adamantanes are not recommended. Within the US, two neuraminidase inhibitors are currently approved for both treatment and prevention, while worldwide there are four available. In this review, we will briefly discuss the epidemiology and pathology of influenza and then discuss neuraminidase inhibitors: their mechanism of action, resistance, development, and future applications.
OBJECTIVE:Timely treatment with neuraminidase inhibitor (NAI) drugs appears to improve survival in adults hospitalized with influenza. We analyzed California surveillance data to determine whether NAI treatment improves survival in critically ill children with influenza.METHODS:We analyzed data abstracted from medical records to characterize the outcomes of patients aged 0 to 17 years hospitalized in ICUs with laboratory-confirmed influenza from April 3, 2009, through September 30, 2012.RESULTS:Seven hundred eighty-four influenza cases aged <18 years hospitalized in ICUs had information on treatment. Ninety percent (532 of 591) of cases during the 2009 H1N1 pandemic (April 3, 2009-August 31, 2010) received NAI treatment compared with 63% (121 of 193) of cases in the postpandemic period (September 1, 2010-September 30, 2012; P < .0001). Of 653 cases NAI-treated, 38 (6%) died compared with 11 (8%) of 131 untreated cases (odds ratio = 0.67, 95% confidence interval: 0.34-1.36). In a multivariate model that included receipt of mechanical ventilation and other factors associated with disease severity, the estimated risk of death was reduced in NAI-treated cases (odds ratio 0.36, 95% confidence interval: 0.16-0.83). Treatment within 48 hours of illness onset was significantly associated with survival (P = .04). Cases with NAI treatment initiated earlier in illness were less likely to die.CONCLUSIONS:Prompt treatment with NAIs may improve survival of children critically ill with influenza. Recent decreased frequency of NAI treatment of influenza may be placing untreated critically ill children at an increased risk of death.